Fibroscan to Guide Post Transplant Immunosuppression Minimization

Overview

Following Liver transplantation, recipients remain on life long immunosuppression. Prolonged exposure to immunosuppression is associated with side effects and complications including kidney dysfunction, diabetes, heart disease and cancer risk. Therefore studies are looking at safe ways to reduce or stop immunosuppression. An individual without autoimmune liver disease (these patients are at higher risk of rejection), without history of rejection, with normal blood tests (liver biochemistry, liver function, etc.) can be eligible for minimization of immunosuppression. A recent study showed use of fibroscan (an Ultrasound, which provides information on liver stiffness (diseased liver is hard while a normal liver is soft) and fat content) provides more objective information to help investigators select individuals who will tolerate immunosuppression minimization. Our goal is to see if use of fibroscan allows the investigators to safely minimize immunosuppression in eligible individuals. The secondary aims are to assess benefit on kidney function, heart disease and risk factors for heart disease.

Excellent short-term survival following liver transplantation (LT) has translated into long-term survival with many patients surviving over 25 years (1). Thus, many patients will have prolonged exposure to immunosuppression (IS), which is a double edged sword and needs to be carefully balanced; inadequate levels may lead to rejection whereas consistently high levels may lead to side effects and long term complications (e.g. metabolic syndrome (MS), renal dysfunction (CKD), cardiovascular disease (CVD), malignancy) (2). Of note, the type of IS used (mTOR inhibitors (mTOR) vs. calcineurin inhibitors (CNI)) may also contribute to complications. Whereas CNI use is associated with renal dysfunction and development of de novo steatosis (3), mTOR use is associated with increased risk of dyslipidemia; combined use of CNI and mTOR has been shown to lead to hyperglycemia (4, 5). Not surprisingly, IS use is associated with development of MS post LT (2, 6). Due to shared risk factors, presence of steatosis may also lead to increased risk of MS, CVD and renal dysfunction. Thus, minimization of IS may lead to reduced complications. Management of IS varies by transplant centre and involves trial and error; most rely on drug levels, liver biochemistry, indication for transplant, duration following transplant, and demographics of the recipient. Changes in IS tend to be reactive in nature and occur in the setting of complications. Studies have shown a substantial number of patients may be able to tolerate lower levels of IS (7, 8). Thus, there is a need for an objective, non-invasive, measure that can help clinicians optimize IS. Vibration-Controlled Transient elastography (TE; FibroScan®) is a promising tool; it is a non-invasive technique for assessment of liver stiffness measurement (LSM) that additionally provides the controlled attenuation parameter (CAP), which reflects hepatic steatosis. TE accurately predicts degree of liver fibrosis and portal hypertension regardless of etiology of liver disease (9-11). In the pre-transplant setting it is a common point-of-care tool that has led to reduced need for liver biopsy, risk stratification of patients with non-alcoholic fatty liver disease (12), and use as a guide to treat patients with Hepatitis B infection (13). The use of TE post LT remains limited with a scarcity of studies. The few studies that exist are limited by a small sample size and short follow up post-LT. Nevertheless, these studies show there is a correlation between TE and severity of acute cellular rejection (r=0.6; p\< 0.001) (10); fibrosis and degree of portal hypertension (14); association with other diseases (idiopathic hepatitis, steatohepatitis, cholangitis, de novo or recurrent disease) (9); association with steatosis (AUROC 0.88) (15); and association with decompensation and graft/patient survival (16). In a recent study, TE was used to identify individuals with low risk of rejection who could safely undergo IS minimization. Authors showed that subclinical allo-immune injury was associated with increased LSM and that patients with LSM below 8.4 kPa had a negligible probability of having active alloimmune damage (11%); these patients could potentially have reduction of IS (7). This study provides the scientific basis for assessing the use of TE as a guide to IS management. The aim of this study is to assess if TE can be used to safely guide IS minimization in stable post-LT patients. The secondary aims will include impact on renal function, MS, CVD, malignancy, graft and patient survival. In a nested study, the investigators will explore the use of TE to investigate the effect of type of immunosuppression used and the development of hepatic steatosis, based on the CAP score (nested case-control study).